The overall organizing hypothesis of this Program posits that bioactive sphingolipids function as important regulators of several key tumor cell attributes, including tumor initiation, differentiation, growth, apoptosis, senescence, inflammation, invasion, and metastasis. As a corollary, enzymes of sphingolipid metabolism are emerging as specific and novel targets in modulating these important cancer attributes. Unfortunately, the study of bioactive lipids is rife with complications, both conceptual and technical and thus the study of lipids necessitates the collaborative interactions of various disciplines and specialized cores. Thus, we have evolved 4 distinct projects that collaborate to investigate the overall hypothesis: Project 1 will address the specific hypothesis that acid sphingomyelinase defines a novel pathway of cancer cell biology involving two specific mediators, the chemokine RANTES and the cytokine IL6, with important roles in cancer inflammation and metastasis. Project 2 will test the specific hypothesis that alkaline ceramidase 1 acts as a tumor suppressor in non-melanoma skin cancers and its downregulation promotes skin tumorigenesis by stimulating hyperproliferation of epidermal keratinocytes. Project 3 will test the hypothesis that loss of Sphingosine Kinase 1 is a key event in mediating the tumor suppressor effects of P53, especially on the induction of senescence. Project 4 will test the hypothesis that BCR-ABL1 transcriptionally regulates SMS1 and that elevated SMS1 activity sustains the tumorigenic potential of BCR-ABL1 positive cells. These 4 projects will be supported by two unique research cores: The Lipidomics Core which will provide analytical and synthetic lipid chemistry, and by a Sphingolipid Animal Cancer Pathobiology Core that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of in vivo carcinogenesis. This Program group has been highly integrated and productive and has advanced significantly our understanding of sphingolipids (one of the last frontiers of basic research) in caner biology and therapeutics. We are now poised to advance pre-clinical studies and translational research based on our understanding of these novel pathways. These studies continue to identify novel targets and strategies for cancer therapeutics.